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  • Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy.

Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy.

Blood (2014-10-23)
Anniek B van der Waart, Noortje M P van de Weem, Frans Maas, Cynthia S M Kramer, Michel G D Kester, J H Frederik Falkenburg, Nicolaas Schaap, Joop H Jansen, Robbert van der Voort, Luca Gattinoni, Willemijn Hobo, Harry Dolstra
ABSTRACT

Effective T-cell therapy against cancer is dependent on the formation of long-lived, stem cell-like T cells with the ability to self-renew and differentiate into potent effector cells. Here, we investigated the in vivo existence of stem cell-like antigen-specific T cells in allogeneic stem cell transplantation (allo-SCT) patients and their ex vivo generation for additive treatment posttransplant. Early after allo-SCT, CD8+ stem cell memory T cells targeting minor histocompatibility antigens (MiHAs) expressed by recipient tumor cells were not detectable, emphasizing the need for improved additive MiHA-specific T-cell therapy. Importantly, MiHA-specific CD8+ T cells with an early CCR7+CD62L+CD45RO+CD27+CD28+CD95+ memory-like phenotype and gene signature could be expanded from naive precursors by inhibiting Akt signaling during ex vivo priming and expansion. This resulted in a MiHA-specific CD8+ T-cell population containing a high proportion of stem cell-like T cells compared with terminal differentiated effector T cells in control cultures. Importantly, these Akt-inhibited MiHA-specific CD8+ T cells showed a superior expansion capacity in vitro and in immunodeficient mice and induced a superior antitumor effect in intrafemural multiple myeloma-bearing mice. These findings provide a rationale for clinical exploitation of ex vivo-generated Akt-inhibited MiHA-specific CD8+ T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Brefeldin A, ≥99% (HPLC and TLC), BioXtra, for molecular biology
Sigma-Aldrich
Brefeldin A, from Penicillium brefeldianum, ≥99% (HPLC and TLC)
Sigma-Aldrich
DL-Glyceraldehyde 3-phosphate solution, 45-55 mg/mL in H2O
Sigma-Aldrich
5-Carboxy-fluorescein diacetate N-succinimidyl ester, for fluorescence, ≥95.0% (HPLC)
Sigma-Aldrich
5(6)-Carboxyfluorescein diacetate N-succinimidyl ester, BioReagent, suitable for fluorescence, ≥90% (HPLC)
Sigma-Aldrich
Brefeldin A, from Penicillium brefeldianum, Ready Made Solution, 10 mg/mL in DMSO